Cathelicidin peptide LL-37 increases UVB-triggered inflammasome activation: Possible implications for rosacea
Introduction
Rosacea is a common, often underdiagnosed, chronic cutaneous disorder that typically affects the convexities of the face, including the cheeks, chin, forehead, and nose [1], [2]. Its course is characterized by transient flushing, persistent erythema, and telangiectasia, in addition to inflammatory papules and pustules and hypertrophy of the sebaceous glands [3]. Ocular changes, in the presence or absence of cutaneous disease, are present in 20% of patients [4]. Based on patterns of symptoms and physical findings, rosacea is divided into four subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular rosacea [5], [6].
Despite distinct classification, the clinical heterogeneity included under the broad rubric of rosacea has obscured our understanding of this condition and a specific cause for rosacea has yet to be elucidated [3], [5]. Nevertheless, factors that aggravate the disease, including UVB radiation, emotional stress, spicy foods, and high temperatures, are well defined, suggesting that the external environment affects rosacea [7]. Recent studies further implicate an altered immune detection and response system in the development of vascular abnormalities and inflammatory disease in patients with rosacea [8], [9].
Exogenous insults and changes normally trigger an innate immune response that includes the controlled increase in cytokines and antimicrobial molecules in the skin [10]. Individuals with rosacea, however, respond with an excessive activation of innate immune effector molecules, including cathelicidin antimicrobial peptides [11], [12]. Cathelicidin peptides possess antimicrobial as well as immunomodulatory properties and are, thus, important contributors to innate host defense [13], [14]. The activity of cathelicidin is regulated by proteolytic processing of the proform hCAP18 to a mature peptide [15]. In addition to expressing abnormally high levels of cathelicidin, proteolytically processed forms found in rosacea patients are different from those found in healthy individuals [11]. LL-37 is the predominant cathelicidin peptide in rosacea and has been shown to be both proinflammatory and vasoactive [11], [16], [17], [18], [19].
In addition to an overexpression of LL-37, evaluation of facial skin of rosacea patients reveals increased expression of genes that signal enhanced sensitivity and reactivity to diverse environmental triggers [7]. Enhanced expression of Toll-like receptor 2 (TLR2), an innate immune sensor that detects pathogen- or danger-associated patterns, has been detected in the epidermis of patients with rosacea [20]. Furthermore, activation of TLR2 in keratinocytes promotes an increase in serine protease kallikrein 5 (KLK5), the enzyme responsible for the proteolytic activation of hCAP18 to LL-37 [20]. While enhanced TLR2 expression may link external insults to cathelicidin-mediated abnormalities, increased expression of inflammasome-related genes suggests that multiple danger recognition mechanisms are simultaneously at play in rosacea [21]. Inflammasomes are immune complexes that form upon activation by multiple types of tissue damage or pathogen-associated signatures [22]. Inflammasome formation results in caspase-1-mediated proteolytic activation of interleukin-1β (IL-1β). A potent immunoregulatory and proinflammatory cytokine, IL-1β has additionally been attributed with proangiogenic properties [23], [24], [25]. Increased expression of IL-1β, therefore, further suggests that augmented immune responses promote inflammation and vascular hyperactivity in rosacea.
Given the critical role of the innate immune system, insight into the ways in which intrinsic factors in the host interact with exogenous triggers to give rise to the clinical picture of rosacea is essential to advancing our understanding of the pathogenesis of the disease. In this study, we investigated how the proinflammatory and proangiogenic effects of UVB irradiation—a notorious aggravating factor in rosacea–are enhanced in the presence of LL-37, the cathelicidin peptide found in excess in the skin of rosacea patients. Our results indicate that UVB radiation, UVB-triggered inflammasome activation, and LL-37 work together to induce an immune response capable of initiating and perpetuating underlying pathophysiological mechanisms in rosacea.
Section snippets
Ex vivo UVB irradiation and immunoblot
Four millimeter punch biopsies were taken from the skin of healthy volunteers and cultured in EpiLife® cell culture medium (Cascade Biologics) containing 0.06 mM Ca2+ and 1 × EpiLife® defined growth supplement (EDGS) at 37 °C under standard tissue culture conditions. After 24 h, skin biopsies were transferred to 4 cm2 tissue culture dishes with phosphate buffered saline (PBS) and exposed to 350 mJ/cm2 UVB radiation emitted by a TL 20 W/12 RS UVB lamp (Philips). Biopsies were subsequently cultured in
UVB induces the release of IL-1β via the inflammasome and this release is augmented in the presence of LL-37
UVB radiation triggers several proinflammatory cascades in the skin and its induction of IL-β in epidermal keratinocytes has been shown to be inflammasome-mediated [27]. Inflammasome activation results in caspase-1-dependent processing of pro-IL-1β to active IL-1β, which is then secreted. Confirming these observations, UVB irradiation of healthy human skin ex vivo resulted in the activation of caspase-1 and the consequent release of IL-1β into the tissue culture medium (Fig. 1A and B). In
Discussion
Rosacea is generally observed in fair-skinned individuals, and those of Celtic and northern European origin are particularly susceptible [4]. Marked intolerance to light is characteristic of the disease, which is consistent with the fact that the distribution of lesions is predominantly limited to sun-exposed sites [33], [34]. UV-induced cutaneous changes include dermal matrix degradation and loss of perivascular structural integrity, with subsequent telangiectasia and erythema [35]. Meanwhile,
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft (Scha 979/5-1) and Else Kroener Fresenius Stiftung (2012_A119).
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2022, HeliyonCitation Excerpt :LL-37 (Cathelicidin antimicrobial peptide) and kallikrein 5 (KLK5) may serve as the key contributors to the proinflammatory and proangiogenic effects, which are highly expressed in the skin of patients with rosacea. Recent studies may pay more attention to the integrated mechanism of their up/downstream molecules (e.g., NLRP3 inflammasome [56], IL-36γ [57], protease-activated receptor 2 (PAR-2) [58], mechanistic target of rapamycin complex 1 (mTORC1) [59]). Additionally, it has also reported high expression of toll-like receptor (TLR) family and matrix metalloproteinases (MMPs) in patients with rosacea.
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2022, Annales de Dermatologie et de VenereologieCitation Excerpt :A study in homozygous twins also shows that lifetime UV exposure is a risk factor for rosacea [102]. A first study already showed that LL-37 increased activation of UVB-dependent inflammasome [109]. IL-33 may be the link between UV exposure, activation of innate immunity and angiogenesis [110].
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2021, Cellular ImmunologyCitation Excerpt :We next investigated the effects of lactic acid in a more severe skin inflammation model of pseudo-allergic rosacea. The cathelicidin LL-37 is elevated in the skin tissues of human patients with rosacea, and consequently, it has been used for inducing the pathogenesis of experimental rosacea in rodents [43–44]. Specifically, Muto et al. [10], showed that the LL-37 injections in the skin causes rosacea like symptoms in mice that are dependent on the presence of mast cells.